ABSTRACT
Antisense and antigene oligonucleotides offer a promising new approach for therapy of cancer, inflammatory diseases, and viral diseases. Due to the large molecular weight and polar nature of oligonucleotides, cellular uptake is potentially the limiting factor for therapeutic utilization. Phosphodiester oligonucleotides reportedly bind to an 80-kDa surface protein and enter cells via receptor-mediated endocytosis. Only a fraction of the cellular accumulated oligonucleotide actually reaches the cytoplasm, by an undefined process that may include diffusion, membrane destabilization, or leakage during vesicle fusion. The physiochemical properties of oligonucleotides are likely to affect membrane transport. However, there are also reports in the literature demonstrating the lack of effect of sequence on cellular uptake. Each of the backbone modifications increases stability, but none have proven to demonstrate clearly superior cellular transport characteristics. Oligonucleotides having the nonyl and pentyl modifications had a definite effect on sucrose fluxes, whereas the other oligonucleotides were essentially without effect.
